Membrane-bound CD95 ligand modulates CD19-mediated B cell receptor signaling and EBV activation
Membrane-bound CD95 ligand modulates CD19-mediated B cell receptor signaling and EBV activation
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膜结合 CD95 配体调节 CD19 介导的 B 细胞受体信号传导和 EBV 激活。
DOI：
10.1002/jmv.29440
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发表时间：
2024-02-01
影响因子：
12.7
通讯作者：
Liang，Xiaozhen
中科院分区：
文献类型：
--
作者：
Liu，Mu;Huang，Chenxu;Liang，Xiaozhen
移植后淋巴细胞增生性疾病（ptld）与eb病毒（EBV）感染有关。大多数来源于EBV永生化B细胞或PTLDs的淋巴母细胞样细胞系（LCLs）对CD95介导的凋亡和细胞毒性T细胞（CTL）杀伤敏感。CD95配体（CD95L）以跨膜配体（mCD95L）或可溶性形式（sCD95L）存在。利用重组mCD95L和sCD95L，我们观察到sCD95L不影响lcl。mCD95L在ctl中的高表达促进lcl细胞凋亡，低表达诱导网格蛋白依赖性CD19内化、半胱天冬酶依赖性CD19裂解以及蛋白酶体/溶酶体依赖性CD19降解。CD95L/CD95介导的CD19降解损害B细胞受体（BCR）信号传导并抑制BCR介导的EBV激活。有趣的是，尽管抑制caspase活性可以恢复CD19表达和CD19介导的BCR激活，但它无法挽救BCR介导的EBV裂解基因表达。EBV特异性ctl工程化过表达mCD95L，对lcl表现出更强的杀伤活性。这项研究强调，工程EBV特异性ctl表达更高水平的mCD95L可能是一种有吸引力的治疗方法，可以改善PTLDs的T细胞免疫治疗。
Post‐transplant lymphoproliferative disorders (PTLDs) are associated with Epstein‐Barr virus (EBV) infection in transplant recipients. Most of lymphoblastoid cell lines (LCLs) derived from EBV‐immortalized B cells or PTLDs are sensitive to CD95‐mediated apoptosis and cytotoxic T cell (CTL) killing. CD95 ligand (CD95L) exists as a transmembrane ligand (mCD95L) or a soluble form (sCD95L). Using recombinant mCD95L and sCD95L, we observed that sCD95L does not affect LCLs. While high expression of mCD95L in CTLs promotes apoptosis of LCLs, low expression induces clathrin‐dependent CD19 internalization, caspase‐dependent CD19 cleavage, and proteasomal/lysosomal‐dependent CD19 degradation. The CD95L/CD95‐mediated CD19 degradation impairs B cell receptor (BCR) signaling and inhibits BCR‐mediated EBV activation. Interestingly, although inhibition of the caspase activity restores CD19 expression and CD19‐mediated BCR activation, it fails to rescue BCR‐mediated EBV lytic gene expression. EBV‐specific CTLs engineered to overexpress mCD95L exhibit a stronger killing activity against LCLs. This study highlights that engineering EBV‐specific CTLs to express a higher level of mCD95L could represent an attractive therapeutic approach to improve T cell immunotherapy for PTLDs.
影响因子：
6.7
作者：
Lv DW;Zhang K;Li R
通讯作者：
Li R
影响因子：
3.7
作者：
Daburon S;Devaud C;Costet P;Morello A;Garrigue-Antar L;Maillasson M;Hargous N;Lapaillerie D;Bonneu M;Dechanet-Merville J;Legembre P;Capone M;Moreau JF;Taupin JL
通讯作者：
Taupin JL
影响因子：
3.7
作者：
Kumar S;van Raam BJ;Salvesen GS;Cieplak P
通讯作者：
Cieplak P